Cancers, for example, gastric cancer, prostate cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, ovarian cancer, cancer of the spleen, testicular cancer, cancer of the thymus, etc., are diseases characterized by abnormal, accelerated growth of epithelial cells. This accelerated growth initially causes a tumor to form. Eventually, metastasis to different organ sites can also occur. Although progress has been made in the diagnosis and treatment of various cancers, these diseases still result in significant mortality.
MET encodes a transmembrane tyrosine kinase receptor for Hepatocyte Growth Factor (HGF, scatter factor), which transduces signals implicated in proliferation, migration and morphogenesis (6-8). Ectopic expression of MET, as well as HGF, confers a tumorigenic and metastatic phenotype in cancer-derived cell lines (9-11), and activating mutations have been reported in both sporadic and inherited forms of renal papillary carcinomas (12). Mutations in MET are rare in breast cancer (13, 14), but tumors with high protein expression appear to have a worse clinical prognosis (15, 16). Furthermore, increased HGF/MET signaling can serve as an initiating event for tumorigenesis, as mice overexpressing either HGF or mutant Met in mammary epithelium develop breast tumors (17-19).
Genetic events that arise and are selected during tumor progression may become essential for tumor survival, a phenomenon generally described as “oncogene addiction” (1). For example, homozygous inactivation of Brca1 alone leads to activation of DNA damage signals and p53-mediated cell cycle arrest; however, simultaneous suppression of p53 allows bypass of this DNA damage checkpoint, and leads to accelerated tumor formation (2-4). The identification of these secondary mutations is important in designing effective treatment for cancers, as targeting one genetic event may not suffice.
It must be remembered that overexpression and amplification are not the same phenomenon. Overexpression can be obtained from a single, unamplified gene, and an amplified gene does not always lead to greater expression levels of mRNA and protein. Thus, it is not possible to predict whether one phenomenon will result in, or is related to, the other. However, in situations where both amplification of a gene and overexpression of the gene product occur in cells or tissues that are in a precancerous or cancerous state, then that gene and its product present both a diagnostic target and a therapeutic opportunity for intervention. Amplification, without overexpression, and overexpression, without amplification, also can be correlated with and indicative of cancers and pre-cancers.
There is a significant need in the art for a satisfactory treatment of cancer, and specifically cancers such as gastric, lung, ovarian, breast, brain, colon and prostate cancers. While tyrosine kinase therapy has proven to be beneficial in many cancer types, its utility is currently limited by our understanding of the individuals in which the therapy is most likely to be effective. Thus, there is a need to identify patients who will most benefit from particular therapies, so as, for example, to limit clinical trial participation to only this subset of individuals and to provide the most appropriate therapy to each individual person in need.